Targeting the progression of mitosis is a highly successful strategy for anticancer treatment (Jackson, J. R., et al., Nat Rev Cancer, 2007. 7 (2): p. 107-17). A closely related subgroup of three serine/threonine kinases, the Aurora kinases, are believed to play a key role in protein phosphorylation in mitosis and have been shown to contribute in the development and progression of cancer. In mammals, the Aurora kinase family comprises three members: Aurora A, B and C (Carmena, M. and W. C. Earnshaw, Nat Rev Mol Cell Biol, 2003. 4 (11): p. 842-54). They display distinct roles during mitosis, which are reflected in their subcellular locations and functions. Aurora A is localized at the centrosome from the time of centrosome duplication through mitotic exit. It has been implicated in several processes required for the generation of bipolar spindle apparatus, including centrosome maturation and separation (Andrews, P. D., Oncogene, 2005. 24 (32): p. 5005-15; and Barr, A. R. and F. Gergely, J Cell Sci, 2007. 120 (Pt 17): p. 2987-96). Small molecule inhibition of Aurora A kinase activity causes defects in centrosome separation with the formation of characteristic monopolar spindles (Marumoto, T., D. Zhang, and H. Saya, Nat Rev Cancer, 2005. 5 (1): p. 42-50). Aurora B is localized to the centromeres from the prophase to the metaphase-anaphase transition. Thereafter, it is localized to midzone spindle microtubules during the telophase and subsequently to midbody during cytokinesis. Aurora B is a chromosomal passenger protein in complex with the inner centromere proteins (INCENP), survivin, and borealin. During mitosis, as the “equatorial-kinase”, Aurora B is required for histone H3 phosphorylation, chromosome bi-orientation, the spindle assembly checkpoint, and cytokinesis (Kallio, M. J., et al., Curr Biol, 2002. 12 (11): p. 900-5; and Carvajal, R. D., A. Tse, and G. K. Schwartz, Clin Cancer Res, 2006. 12 (23): p. 6869-75). Inhibition of Aurora B kinase activity with small molecules leads to failure in cytokinesis and abnormal exit from mitosis, resulting in endoreduplication, polyploidy cells, and ultimately apoptosis (Hauf, S., et al., J Cell Biol, 2003. 161 (2): p. 281-94; and Ditchfield, C., et al., J Cell Biol, 2003. 161 (2): p. 267-80). Aurora C is also a chromosomal passenger protein considered to have a similar sub-cellular location as Aurora B. It has been described only in mammals, where it is expressed in testis and certain tumor cell lines and localizes to spindle poles during late mitosis (Carmena, M. and W. C. Earnshaw, Nat Rev Mol Cell Biol, 2003. 4 (11): p. 842-54; and Chen, H. L., et al., J Biomed Sci, 2005. 12 (2): p. 297-310).
Inhibition of Aurora kinases had been shown to be an effective strategy for anticancer therapy, and several Aurora inhibitors have been described, including VX-680 (Harrington, E. A., et al., Nat Med, 2004. 10 (3): p. 262-7), Hesperadin (Hauf, S., et al., J Cell Biol, 2003. 161 (2): p. 281-94), AZD1152 (Yang, J., et al., Blood, 2007. 110 (6): p. 2034-40), and MLN8237 (Gorgun, G., et al., Blood, 2010. 115 (25): p. 5202-13.). More than 30 small molecule Aurora kinase inhibitors are currently in different stages of preclinical and clinical development (Kollareddy, M., et al., Invest New Drugs, 2012), however, none have yet been approved by the FDA for clinical use.
Currently there is a need for agents that are useful for treating or preventing cancer.